Conductive polymer doped by a sulphonated cyclodextrin salt and device for obtaining and/or supplying an active substance incorporating said polymer

ABSTRACT

Conductive polymer doped by a sulphonated cyclodextrin salt and device for obtaining and/or supplying an active substance incorporating said polymer. The dopant used has the following formula (I): ##STR1## in which n is an integer between 2 and 50, M +  is Na + , Li + , K +  Mg +  1/2 or NH 4   +  and R represents --SO 3   -  M +  or --OH, whereby R can differ from one cycle to the other. The doped conductive polymer can be used as an active electrode material in an electrochemical device.

DESCRIPTION

The present invention relates to novel electronically conductivepolymers doped by a sulphonated cyclodextrin salt usable in numerousfields in view of their conductive properties. Thus, said polymers canconstitute an active electrode material in an electrochemical device.More specifically, these electrochemical devices are intended to collector obtain and/or salt out an active substance. Thus, the polymersaccording to the invention can be used in the pharmaceutical,veterinary, chemical and nuclear fields.

As known electricity conducting, organic polymers reference can be madeto polyacetylenes, polypyrroles, polyanilines and polythiophenes.

These conductive polymers are generally prepared by a chemical orelectrochemical oxidation of the corresponding monomer dissolved in anappropriate solvent containing a simple or complex, doping anion. Theseanions are in particular the ions SO₄ ²⁻, F, Cl⁻, BF₄ ⁻, PF₆ ⁻, ClO₄ ⁻,Br⁻ as described in document (1), i.e. FR-A-2 622 601.

It is also known to use cyclodextrins for forming inclusion compoundswith numerous organic substances and in particular liquid organicproducts having a limited solubility in water. In this connectionreference can be made to document (2), U.S. Pat. No. 3,426,011; document(3) "Synthese und Charakterisierung von Per(3,6-anhydro)cyclodextrinen"by P. R. Ashton et al, Angew. Chem., 103, no. 1, 1991, pp.96-97; anddocument (4) "Sulfation and hemolytic activity of cyclodextrin" by E. J.Macarak, Biochemical Pharmacology, vol. 42, no. 7, pp.1502-1503, 1991.

It is also known from document (5), i.e. U.S. Pat. No. 4,755,326 to usecyclodextrin in an electronically conductive polymer doped by an ion ofan alkali metal with a view to increasing the electrical conductive ofconductive polymers such as polyacetylenes and polypyrones.

It is pointed out that cyclodextrins are cyclic oligosaccharides ofD-glucose usually having 6 to 8 D-glucopyranosyl units linked by α-(1→4)linkages, which gives them a toroidal morphology. As a result of thismolecular arrangement and the afferent electronic structures, ahydrophobic character is associated with the internal cavity of thecycle, whereas the outer surface of the molecule is hydrophilic.

It is also known that the solubility of cyclodextrins in water andconsequently that of their inclusion products are significantlyincreased when the molecule is substituted by hydrophilic groups. Thisis in particular the case with cyclodextrins having (aminated orsulphated) charged, polar groups.

In addition, sulphonated derivatives of linear monosaccharides have longbeen known, in particular from document (6), Carbohydrate Research, 22(1972), pp.23-35 by J. Lehmann and W. Weekerie, "Zuckersulfonsauren";document (7), M. Myano and A. Benson, J. Am: Chem. Soc., 84, 59, 1972,pp.57-62 "The plant sulfolipid. VI. Configuration of the glycerolmoiety"; document (8), R. Whistler and D. Mealcalf, Archives ofBiochemistry and Biophysics 105, 1964, pp.1-6, "Preparation of6-deoxyamilose-6-sulfonic acid".

The invention relates to novel electronic conductive polymers doped by adopant giving a high conductivity to said polymers, as well as activesubstance collecting properties, permitting their use in devices forcollecting and/or salting out active substances and in particularmedicaments, in an electrochemical manner.

According to an essential feature of the invention, the novelelectronically conductive polymers are doped by a cyclodextrin having atleast one sulphonate group.

The dopant according to the invention can have one or more sulphonategroups arranged in symmetrical or non-symmetrical manner on the completeoligosaccharide as a function of the specific application envisaged.

In addition, the polymers according to the invention have a highstability and can be oriented in an electric field.

Advantageously, the dopant of the conductive polymers is of formula (I):##STR2## in which n is an integer from 2 to 50, M⁺ is an ion chosen fromamong Na⁺, Li⁺, K⁺, NH₄ ⁺ and Mg⁺ 1/2 and R represents --SO₃ ⁻ M⁺ or--OH and R can differ from one cycle to the next. In particular, n is 2to 10, preferably 5, 6 or 7.

These sulphonated cyclodextrins can be prepared very simply, unlikecertain prior art cyclodextrins (cf. particularly document (2)), byreacting the sulphite of sodium, lithium (Li₂ SO₃, H₂ O), potassium (K₂SO₃, 2H₂ O), magnesium (MgSO₃, 6H₂ O) or ammonium ((NH₄)₂ SO₃ or NH₄HSO₃) on a halide of a corresponding cyclomalto-oligosaccharide, in thepresence of a phase transfer agent, said halide having at least onehalogen atom in the 6-position of a glucose cycle. This leads to thecorresponding cyclodextrin salt.

In this process, use is made of direct micellization properties.

The 6-halo derivatives are obtained according to known processes. Inaddition, the exchange reaction of a halide for a sulphonate has beenknown for some time in organic chemistry.

The halide can be an iodide, a bromide or a chloride. It can bemonohalogenated, partly halogenated or perhalogenated. The position ofthe halogens in the starting cyclomalto-oligosaccharide fixes theposition of the sulphonate groups.

Advantageously, the reaction is performed in an aqueous medium, thephase transfer agent ensuring the dissolving of thecyclomalto-oligosaccharide halide, which is normally insoluble in water.

It is pointed out that a transfer agent, also known as a surfactant, isa compound having a polar head and a sufficiently long hydrophobic chainleading to respectively highly marked hydrophilic and lipophilictendencies. Thus, the dissolving of a small surfactant quantity in asolvent leads to a pronounced reduction in the surface tension. Thus,surfactant solutions are able to incorporate large quantities ofcompounds normally insoluble in the medium in question.

In order to assist the approach of the sulphite anion solubilized inwater to the halo-sulphodextrins, use is preferably made of a surfactantwith a polar head positively charged by a quaternary ammonium group. Thehydrophobic part has long chain alkyl groups with 4 to 12 carbon atoms.

The counterion of the surfactant can be chosen from among the sulphate,sulphite, iodide, chloride, bromide or acetate anion.

It is also possible to obtain the salts of Li, K, Mg and ammonium of thecyclodextrin by starting with the sodium salt, i.e. a cyclodextrinsulphonate sodium solution by exchange on an ion exchange column inorder to replace the Na⁺ cation by the desired cation.

In the case of the ammonium cation, it is possible to work in thefollowing way. Using an ammonia solution in the form NH₄ ⁺, exchangetakes place of an acid resin column, e.g. an AMBERLITE 77H⁺ resin. Thisis followed by the deposition on the column, which contains 50 times thesodium equivalent to be exchanged, the sodium sulphonate solution,followed by eluting the column with water. The eluate obtained is theammonium sulphonate of the cyclodextrin.

It is possible to work in the same way with other cations.

The polymers to be doped and which are usable in the invention can becopolymers or homopolymers, which can be prepared in a liquid medium andin particular an aqueous medium. Thus, the polymers according to theinvention can be polypyrroles, polyanilines and polythiophenes, whichcan be prepared by the chemical or electrochemical oxidation of thecorresponding monomers in the solvent medium.

The term "polypyrrole", "polyaniline" and "polythiophene" is used todesignate homopolymers and copolymers respectively of pyrrole and/or itsderivatives, aniline and/or its derivatives such aspara(aminodiphenylamine), toluidines, aminophenols and carboxyanilines,thiophene and/or its derivatives such as bithiophene andalkyl-3-thiophenes having 1 to 12 carbon atoms.

Due to the sulphonate groups of the electronic dopant, the cyclodextrinsaccording to the invention have a high solubility in water, whichpermits the use of this solvent for the production of the polymersaccording to the invention. However, it is also possible to use othersolvents such as acid solutions, e.g. of sulphuric or perchlorate acid,or organic solvents such as acetonitrile or dichloromethane.

As a result of the complexing cavity of the cyclodextrins according tothe invention, the doped polymers according to the invention can be usedfor collecting or obtaining an active substance. The invention alsorelates to an apparatus for obtaining an active substance having aconductive polymer as defined hereinbefore, constituting an activeelectrode material and means for controlling the obtaining of saidsubstance by the polymer.

Moreover, as a result of the electronic properties of the conductivepolymer (i.e. polythiophenes, polypyrroles, polyanilines, etc.), thedoped polymers according to the invention can be used for salting outthe previously collected active substance. The invention also relates toan apparatus for supplying an active substance, incorporating aconductive polymer doped in the manner described hereinbefore,constituting an active electrode material and containing said activesubstance and means for controlling the supply of said substance.

According to the invention, the collecting apparatus and the supplyapparatus for an active substance can be the same or differentapparatuses.

The electrochemical apparatuses for collecting and supplying the activesubstance usable in the present invention are those conventionally usedin the medical field, in which the existing positive electrode activematerial is replaced by a polymer film according to the invention.Examples of such apparatuses are described in documents (9) U.S. Pat.No. 5,002,067; (10) EP-A-60 451 and (11) FR-A-2 586 813.

The active substances which can be collected and/or salted out using theapparatus according to the invention are in particular neuroleptics usedfor the treatment of epilepsy, geriatrics and against tumours,diuretics, antihypertensive agents and antidepressants.

BRIEF DESCRIPTION OF THE DRAWINGS

Other features and advantages of the invention can be gathered from thefollowing non-limitative, illustrative description with reference to theattached drawings, wherein show:

FIG. 1 Diagrammatically an apparatus permitting the production of aconductive polymer according to the invention, as well as itscharacterization

FIG. 2 A cyclic voltametric curve giving the variations of the currentdensity J in mA/cm² of a polypyrrole film according to the inventiondoped by a sulphonated β-cyclodextrin, in the presence of an aqueouslithium perchlorate solution, as a function of the voltage U in voltsapplied to said film and measured relative to the reference silverelectrode.

FIG. 3 The evolution of the redox behaviour during a cycling of apolypyrrole film doped by a sulphonated β-cyclodextrin in an aqueouslithium perchlorate solution, following the collecting of N-methylphenothiazine (NMP), curves I to VII giving for 7 cycles the variationsof the current I in μA as a function of the voltage U in volts appliedto the polypyrrole film and measured relative to the silver electrode.

In exemplified manner, a description will now be given of the productionof a polypyrrole film doped by theheptakis-(6-deoxy-6-sulphonyl)-cyciomaltoheptose sodium salt byelectrochemical pyrrole oxidation in the presence of said salt.

For this purpose into a tight, insulating container 2 is introduced abidistilled aqueous solution 4 of said cyclodextrin salt, at a rate of0.01 mole/dm³ and pyrrole at a rate of 0.1 mole/dm³. When the monomerand cyclodextrin have been dissolved, degassing takes place with usingnitrogen for 10 minutes.

Into the electrolyte 4 is then introduced a platinum working electrode 6serving as the anode, an auxiliary electrode 8 serving as the cathodeand a silver reference electrode 10. The electrodes 6 and 8 areconnected outside the container 2 respectively to the positive pole andthe negative pole of a power supply 12.

In order to measure the potential difference between the referenceelectrode 10 and the working electrode 6, a voltmeter 14 is connectedbetween these electrodes 6 and 10. The current or current densityflowing between the electrodes 6 and 8 is measured with the aid of anammeter connected in series (not shown) or read directly on the powersupply 12.

In known manner, the reference electrode 10 has a silver wire 16immersed in a solution 18 of LiCIO₄ and AgNO₃ with an Ag⁺ ionconcentration of 10⁻² M.

With the aid of the power supply 12, a constant potential of 0.4relative to the reference electrode 10 is applied. The maximum synthesischarge is 0.7C/cm². Above said maximum charge, the doped polypyrrolefilm 20 obtained no longer adheres to the surface of the electrode 6.

The electrode 6 covered with the doped film is then rinsed with theelectrolytic solution used either for the electrochemicalcharacterization of the film, or for the electrochemical collecting ofan active substance. This electrolytic solution is in particular lithiumperchlorate dissolved in water at a rate of 0.5 mole/dm³.

The characterization of the film by cyclic voltammetry is carried outwith the aid of an apparatus identical to that of FIG. 1 in which thesolution of sulphonated cyclodextrin salt and pyrrole is replaced by thelithium perchlorate solution. After dissolving the lithium perchloratein water, the solution obtained is alegassed with nitrogen for 10minutes.

By performing a potential sweep between -1.2 and -0.2 volts at a speedof 50 mV/s, for the doped polypyrrole prepared in the aforementionedmanner, the curve shown in FIG. 2 was obtained.

This curve clearly indicates that the sulphonated β-cyclodextrin givesthe polypyrrole film conductive properties. The polypyrrole film had athickness of 1/10 mm corresponding to a synthesis charge of 0.7C/cm².

The electrode 6, covered with the doped polypyrrole film 20, followingits characterization, can then be used for collecting or obtaining aneutral molecule which is insoluble in water, namely N-methylphenothiazine (NMP) of formula (11): ##STR3##

This species belongs to a family of molecules, the phenothiazines, whichhave important applications in the pharmacological field.

For this purpose, the electrode 6 provided with the polypyrrole film 20is reduced in the lithium perchlorate characterization solution, byapplying a voltage of -1.2 V with the aid of the power supply 12,measured relative to the reference electrode. This voltage is maintaineduntil no further reduction current of the doped polypyrrole film ifmeasured.

The electrode 6 with the film 20 in the reduced state is thentransferred into a solution having a known concentration of the speciesto be collected, in this case NMP, at a rate of 0.1 mole/dm³ dissolvedin acetonitrile, for a given time of in this case 90 minutes,accompanied by stirring and under an inert argon or nitrogen atmosphere.The electrode is then left at this potential, i.e. no potential isapplied to it.

Following the collecting of the chemical species by the dopedpolypyrrole film, said film is rinsed in a solution in which thecollected species is insoluble or only very slightly soluble and havinga high ionic force in order to prevent the decomplexing of the collectedspecies by the sulphonated β-cyclodextrin salt.

For NMP, use is made of aqueous lithium perchlorate solutions with aconcentration of 0.5 mole/dm³.

The function of this rinsing solution is to remove the species adsorbedon the surface of the film on the electrode. Rinsing is performed for agiven time of approximately 45 minutes, accompanied by stirring and inan inert atmosphere in the present case.

The electrochemical characterization of the doped polypyrrole film whichhas collected the NMP was performed by cyclic voltammetry using theapparatus of FIG. 1. FIG. 3 corresponds to said voltammetrycharacterization.

Curves I to VII of FIG. 3 were plotted during 7 cycles at a potentialsweep rate of 20 mV/s in a 0.5 mole/l aqueous lithium perchloratesolution. These curves 3 in particular reveal the NMP salting outprocess to the electrolytic solution during cycling. In these curves,PPy designates the doped polypyrrole.

The production of the doped polypyrrole film 20 as the active electrodematerial 6 for obtaining and/or salting out an active substancedescribed hereinbefore started with an aqueous sulphonatedβ-cyclodextrin solution.

The following examples describe the production of a few sulphonatedderivatives usable in the invention.

PRELIMINARY EXAMPLE

Preparation of the phase transfer solution.

44.2 g (i.e. 0.1 mole/l) of methyl trioctyl ammonium chloride weredissolved in 500 ml of water and treated by 60 g of basic resin of typeDowex® SBR OH⁻ for 0.25 h. The resin was then removed by filtration andcarefully rinsed with distilled water. The combined filtrates areneutralized by a 2N sulphuric acid solution. This neutralization isfollowed by potentiometry. The emulsion volume obtained is topped up to1.5 liters and its pH adjusted to 6.5 by adding a 1N soda solution. Thisstable surfactant emulsion is used directly in the operating proceduresdescribed hereinafter of preparing the sulphonatedcyclomalto-oligosaccharide sodium salt.

EXAMPLE 1

Synthesis of heptakis-(6-deoxy-6-Sulphonyl)-cyclomalto-heptaose sodiumsalt.

To 120 ml of the aforementioned surfactant are added 900 mg (7.14 mmole)of sodium sulphite and 900 mg (3.31 mequiv.) ofheptakis-(6-deoxy-6-iodo)-cyclomalto-heptaose prepared according to theoperating procedure described by A. Gadele and J. Deraye in document (9)Angew. Chem. Int. Ed. Engl., 30, pp.78-80, 1991, "Selective halogenationat primary positions of cyclomalto-oligosaccharides and a synthesis ofper-3,6-anhydro-cyclomalto-oligosaccharides".

The mixture was heated to 100° C. for 24 h. After cooling, the reacticnmixture is extracted by dichloromethane in two passages of 100 ml each.The organic fraction is brought to dryness (i.e. 4.2 g) and, apart fromthe surfactant, it containsheptakis-(6-deoxy-6-sulphonyl)-cyclomalto-heptaose.

To this organic residue are added 1 ml of DMSO and an organic mixturecontaining 250 ml of methanol, 150 ml of acetone and 1 ml of aqueous 4Nsoda solution. The cloudy solution obtained is then centrifuged at 5000r.p.m. for 20 min. The sediments recovered are dissolved in distilledwater and the filtered solution is lyophilized.

A NMR spectrum of ¹³ C reveals the presence of theheptakis-(6-deoxy-6-sulphonyl)-cyclomalto-heptaose sodium salt, whereof700 mg are obtained, which corresponds to an 85% yield, based on thestarting halide.

EXAMPLE 2

Synthesis of the heptakis-(6-deoxy-6-sulphonyl)-cyclomalto-hexaose,sodium salt.

To 120 ml of the aforementioned surfactant emulsion are added 900 mg(7.14 mmole) of sodium sulphite and 900 mg (3.31 mequiv.) ofheptakis-(6-deoxy-6-iodo)-cyclomalto-hexaose prepared as in document(8). The mixture is heated to 100° C. during 24 h. After cooling, thereaction mixture is extracted by dichloromethane in two passages of 100ml each. The organic fraction is brought to dryness (i.e. 4.2 g) and,apart from the surfactant, it containsheptakis-(6-deoxy-6-sulphonyl)-cyclomalto-hexaose.

The organic residue obtained is then treated as in example 1.

A NMR spectrum of ¹³ C reveals the presence of theheptakis-(6-deoxy-6-sulphonyl)-cyclomalto-hexaose sodium salt in aquantity of 653 mg, which corresponds to a yield of 80%, based on thestarting halide.

EXAMPLE 3

Synthesis of the heptakis-(6-sulphonyl)-cyclomalto-heptaose sodium salt.

The 900 mg of heptakis-(6-deoxy-6-iodo)-cyclomalto-heptaose of example 3are replaced by 750 mg of heptakis-(6-bromo-6-deoxy)-cyclomaltoheptaose.

The product obtained has the same physical characteristics as thatobtained from the corresponding iodine derivative of example 1.

We claim:
 1. Electrically conductive polymer doped by a dopant,characterized in that the dopant is a cyclodextrin having at least onesulphonate group.
 2. Polymer according to claim 1, characterized in thatthe dopant has the following formula (I): ##STR4## in which n is aninteger from 2 to 50, M⁺ is an ion chosen from among Na⁺, Li⁺, K⁺, NH₄ ⁺and Mg 1/2⁺ and R represents --SO₃ ⁻ M⁺ or --OH and in which R candiffer from one cycle to the next.
 3. Polymer according to claim 2,characterized in that M⁺ is Na⁺.
 4. Polymer according to claim 2,characterized in that n is 2 to
 10. 5. Polymer according to claim 2,characterized in that n is 5, 6 or
 7. 6. Polymer according to claim 2,characterized in that R=--SO₃ ⁻ Na⁺ for all the cycles and n is 5 or 6.7. Polymer according to either of the claims 1 and 2, characterized inthat the polymer is a homopolymer or copolymer of a monomer chosen fromamong pyrrole, thiophene, bithiophene, aniline, para(aminodiphenylamine)and their derivatives.
 8. Polymer according to claim 7 characterized inthat the polymer is a polypyrrole.
 9. Polymer according to claim 7characterized in that it is obtained by the electrochemical oxidation ofa monomer polymerizable in a liquid medium containing cyclodextrin. 10.Polymer according to claim 7 characterized in that the dopant containsan active substance.